Type I Interferon-Regulated T Helper Development

描述（由申请人提供）：CD4+ T辅助细胞（Th）通过分泌特定的细胞因子亚群来调节适应性细胞介导免疫的多个方面。虽然CD4+ T细胞的活性在对病原生物的反应中至关重要，但它们也可以介导与各种炎症过程相关的病理。具体来说，Th2细胞是通过分泌效应细胞因子IL-4、IL-5和IL-13来协调哮喘炎症的关键细胞亚群。IL-4通过诱导关键转录因子GATA3来驱动CD4+ T细胞中Th2的发育。与先天细胞因子IL-12和IFN-3不同，我们最近证明I型干扰素（IFN-1/2）抑制il -4驱动的Th2细胞的发育和表型稳定性。我们进一步证明IFN-1通过抑制GATA3的表达来阻断这一发育途径。基于我们的研究结果，我们提出IFN-1/2可以阻断哮喘Th2细胞的细胞因子分泌，逆转体内的致病作用。我们将通过以下目标来解决这一假设：目的1：表征IFN-1/2重定向的Th2细胞的表型和功能。目的2：确定IFN-1/2阻断GATA3表达的分子机制。目的3：确定IFN-1/2抑制哮喘患者Th2细胞表型稳定性和细胞因子分泌的能力。这些研究的结果将为治疗涉及IFN-1/2的哮喘的新治疗方法奠定基础。

DESCRIPTION (provided by applicant): CD4+ T helper (Th) cells regulate multiple aspects of adaptive cell mediated immunity through the secretion of specific subsets of cytokines. While their activities are critical in responses to pathogenic organisms, CD4+ T cells can also mediate pathologies associated with various inflammatory processes. Specifically, Th2 cells are the key subset of cells that orchestrate the inflammation of asthma through the secretion of the effector cytokines IL-4, IL-5, and IL-13. IL-4 drives Th2 development in CD4+ T cells through the induction of a key transcription factor GATA3. Unlike the innate cytokines IL-12 and IFN-3, we have recently demonstrated that type I interferon (IFN-1/2) inhibits the development and phenotype stability of IL-4-driven Th2 cells. We further demonstrate that IFN-1 blocks this developmental pathway by repressing GATA3 expression. Based on our findings, we propose that IFN-1/2 could block cytokine secretion of asthmatic Th2 cells and reverse the pathogenic effects in vivo. We will address this hypothesis with the following aims: Aim 1: Characterize the phenotype and function of Th2 cells undergoing redirection with IFN-1/2. Aim 2: Determine the molecular mechanism by which IFN-1/2 blocks GATA3 expression. Aim 3: Determine the ability of IFN-1/2 to inhibit phenotype stability and cytokine secretion from Th2 cells isolated from asthmatic patients. The results from these studies will form the basis for new therapeutic approaches to treat asthma involving IFN-1/2.